This mentored clinical scientist research career development award is designed to advance the candidate toward a career as an independent scientist while investigating serotonergic mechanisms of cortical activation as they may pertain to sleep-wake regulation and epilepsy. Neurons in the medulla and midbrain of the brain that contain the neurotransmitter serotonin (5-HT) are central chemoreceptors that sense changes in blood carbon dioxide (CO2) concentration and pH. In the medulla, 5-HT neurons modulate breathing in response to changes in CO2 concentration, or pH. The reason for the chemosensitivity of midbrain 5-HT neurons was not known; however, we now have data to suggest it mediates an arousal response to elevated CO2 concentrations. 5-HT has also been implicated in epilepsy. Given the involvement with sleep-wake regulation, respiratory control and seizure susceptibility, 5-HT neuron dysfunction has been proposed to underlie the pathophysiology of sudden unexpected death in epilepsy (SUDEP), a devastating disease that results in premature death. To date there is a paucity of animal models to study SUDEP. This research proposal seeks to understand the role of 5-HT neurons, especially in their capacity as central chemoreceptors, in the regulation of sleep-wakefulness and breathing following a seizure. In doing this the specific 5-HT mechanisms in the arousal response to CO2 will also be elucidated. A variety of anatomical, surgical, electrophysiological and behavioral techniques will be employed in two different genetically altered mouse lines in which 5-HT neurons are either absent from birth or can be acutely silenced later in life. Completion of the proposed work will ideally lead to improved prophylactic measures in individuals at risk for SIDS and SUDEP and prevent untimely death. The candidate has recruited an outstanding group of mentors and advisors that will guide experimental design, execution of experiments, and analysis of results. For career development, this mentor and advisor team will continue to support the candidate as he develops an independent research program within the Department of Neurology at the Yale School of Medicine relevant to the regulation of sleep and wakefulness and the regulation of consciousness following seizures. Expertise gained in surgical, behavioral, and electrophysiological techniques through coursework, seminars and national conferences as part of this mentored award will carry the candidate into his career as an independent neuroscientist. PUBLIC HEALTH RELEVANCE: Dysfunction of serotonin neurons has been proposed to underly the pathophysiology of certain disease entities such as sudden infant death syndrome (SIDS) and sudden unexpected death in epilpesy (SUDEP). These are two devastating clinical entities that result in death and that we do not understand the pathophysiology of or therefore how they can be prevented. Answers to the questions posed within this proposal, in conjunction with work of others to better identify the populations at risk for death from these diseases, will help to devise prophylactic measures to reduce mortality from these entities.